1. Field of the Invention
The presently disclosed and claimed inventive concept(s) relates generally to compositions having antiproliferative activity, and in particular, but not by way of limitation, to compositions comprising curcumin analogs that possess antiproliferative activity, and methods of producing and using same.
2. Description of the Background Art
Cancer remains a challenging health care problem. Chemotherapeutic drugs are the mainstay in managing patients diagnosed with any form of cancer. Among various malignancies, pancreatic and lung cancers are the leading cause of cancer deaths in the world. For instance, in the United States of America an estimated 160,390 deaths in 2007 were attributed to lung cancer. About 6 out of 10 people with lung cancer die within one year of being diagnosed with the disease. In non-small cell lung carcinoma (NSCLC), which histologically includes adenocarcinoma, squamous cell carcionoma, and large cell carcinoma, surgery is the only curative treatment modality. Meta-analysis of clinical data suggests that up to 85% of the NSCLC patients depend on systemic chemotherapy as part of the overall management. Similarly, pancreatic adenocarcinoma is one of the most lethal cancers, with most patients dying of their disease within one year. The currently available U.S. Food and Drug Administration-approved treatments for this disease are gemcitabine and erlotinib, both of which produce responses only in a minority of patients, and their effect on survival is minimal. In light of the inefficacy of current standard of care in cancer chemotherapy, development of better therapies for pancreatic and lung cancer is of contemporary interest.
Chalcones are open-chain molecules where two aromatic rings flank a three-carbon enone fragment on either side. Curcumin, (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione, is a naturally occurring bis-chalcone derivative present in Curcuma longa Linn, a commonly used Indian spice turmeric. Studies have shown that curcumin has potent anti-angiogenic, anti-cancer properties. Although several in vitro investigations and pre-clinical studies have demonstrated immense potential of curcumin in cancer treatment, its clinical application has been found limited by its instability and poor bioavailability. As such, to improve the spectrum of activity as well as to modify pharmaceutical properties, several structurally-related compounds have been synthesized and evaluated as anti-proliferative and anti-infective agents. See, for example, Adams et al., 2004; Du et al., 2006; Modzelewska et al., 2006; and Robinson et al., 2005. A few curcumin analogs act as anti-inflammatory molecules by inhibiting cyclooxygenase-2 (COX-2) activity. Incidentally, COX-2 is also over-expressed in many malignant tissues. Curcumin has also been found to have beneficial effects in Alzheimer's disease.
3,5-Bis(2-fluorobenzylidene)-4-piperidone (also known as EF24) is a synthetic analog of curcumin that has been shown to possess potent antiproliferative activity against a number of cancer cell lines such as colon, breast and ovarian cell lines. Like curcumin, the exact mechanism of action of EF24 is unclear, but it appears to suppress cancer cell proliferation and angiogenesis by downregulating various cancer promoting genes such as COX-2, IN-8 and VEGF. It has also been found to induce G2/M cell cycle arrest and apoptosis in cisplatin-resistant human cancer cells. A recent study suggests that EF24 suppresses NF-kB signaling by directly inhibiting I-kB kinase. Chemically, it has been proposed that conjugated enones inhibit glutathione-S-transferase, which enhances the cytotoxicity of these compounds. The enones permit addition of intracellular thiol compounds, such as glutathione, to the olefinic double bond. The addition product is capable of further reacting with cellular nucleophiles, and consequently contributes to the cytotoxicity thereof. Definite evidence in favor of this hypothesis is still lacking.
Therefore, there is a need in the art for new and improved antiproliferative compositions. It is to said compositions, as well as methods of producing and using same, that the presently disclosed and claimed inventive concept(s) is directed.